The broad objective of this RFA is to increase our understanding of the factors involved in the transition from drug use to drug dependence (the "switch"). Few clinical studies have sought to examine directly factors in humans that may differentiate individuals who intensify their use to a state of dependence compared to those who sustain regular, but controlled, patterns of use. Cocaine dependence is an excellent model system for examination of factors underlying drug dependence as cocaine is highly reinforcing, is used in binges- indicative of a loss of control, and its abuse is a persistent public health problem. The present application will employ an array of psychiatric, behavioral, pharmacological and pharmacokinetic technologies to examine differences between carefully-matched cocaine users with and without cocaine dependence under controlled inpatient laboratory conditions. These studies capitalize upon preclinical paradigms designed to assess drug-seeking behavior including self-administration and priming procedures. Experiment I will compare cocaine-dependent users to sporadic users (n=12/group) on measures of impulsivity and sensation seeking, direct pharmacodynamic and pharmacokinetic response to intravenous cocaine, and on indices of cocaine-seeking in both a relapse choice self-administration procedure and a progressive ratio self-administration procedure with cocaine. Outcome measures for the behavioral paradigms will include the rate of drug-taking, break-point, and estimates of relative reinforcing value in the presence of alternative reinforcers. In addition, novel measures of loss of control, which contrast the subjects' intent about drug use and their actual drug-seeking behavior, will be examined. Experiment II will compare separate groups of cocaine- dependent individuals to carefully-matched, sporadic cocaine using individuals (n=12/group) on their relative susceptibility or resilience to priming-induced cocaine-seeking. The priming effects of cocaine, alcohol and heroin on cocaine-seeking will be examined in a relapse choice procedure. In addition to this primary outcome, measures of impulsivity and sensation-seeking will be used to examine group differences and as correlates for behavioral outcomes as in Experiment I, and group comparisons will be made for pharmacodynamic and pharmacokinetic differences to cocaine, alcohol and heroin. These studies will provide novel information about differences between cocaine-dependent individuals who demonstrate a loss of control over drug use (i.e., those for whom the "switch" is on) to individuals who are able to maintain a regular and controlled pattern of cocaine use (i.e., those for whom the "switch" is off). Overall, these projects may identify factors that are predictive of the loss of control in cocaine use and may identify fundamental pharmacological or behavioral factors that differentiate individuals who do from those who do not transition to cocaine dependence.